Vaccinia virus (VV) is a member of the poxviridae family with approximately 95% homology to the human pathogen variola virus, the causative agent of smallpox, declared eradicated in 1980. VV has been used for the protective immunization of individuals against smallpox for well over 100 years until its routine use was suspended in the 1970s. However, recent events have resulted in a rethinking of the immunization of healthcare workers as well as the general population, as the threat of the intentional release of variola virus as a bioterrorism weapon has become a potential reality. Interestingly, although VV has been used as a vaccine, the immune response to the virus, considering the state of the art of immunology at the time it was routinely used in the general population, has really been poorly characterized. For example, although it is known that VV induces a cytotoxic T lymphocyte (CTL) response that peaks within one week post-infection, the immunodominant (or subdominant) major histocompatibility complex (MHC) class I-presented peptides are completely unknown. Furthermore, the effects of a VV infection on various aspects of the innate immune response (e.g., NK and NKT cells), have not been extensively studied. Our hypothesis is that VV is capable of inhibiting components of both the innate and adaptive immune responses that could ultimately compromise the optimum level of protection afforded by a VV-based vaccine. To test this hypothesis, the following specific aims are proposed: 1. Determine the mechanism(s) by which CD1d1-mediated antigen presentation to NKT cells is altered following a VV infection, 2. Identify immunodominant and subdominant MHC class I VV epitopes presented to VV-specific CTL, and 3. Analyze the mechanism(s) responsible for the VV-induced reduction in MHC class 1-mediated antigen presentation to CTL. These studies will identify specific targets in the innate and adaptive antiviral immune response that VV and other poxviruses use to evade host immunity. This project is an integral part of the highly interactive and complementary Program Project entitled, "Poxvirus Modulation of Immune Responses". Its role in understanding the inhibitory effects of a poxvirus infection on the innate and adaptive immune responses will be critical information needed in the design of new generation and highly effective VV-based vaccines that would also be protective in the event of an intentional exposure of a population to variola virus.